Numerous genetic and molecular studies have demonstrated that poorly regulated synaptic protein synthesis downstream of metabotropic glutamate receptor 5 (mGlu5) contributes to the pathophysiology of fragile X (FX), a genetic cause of intellectual disability (ID) and autism spectrum disorder (ASD) (Pop et al., 2014). These studies suggest that targeting mGlu5 or its downstream effectors may be a fruitful approach for improving the course of FX and other genetic syndromes with shared pathophysiology (Aguilar-Valles et al., J. Neurosci. 31, 11125-32 (2015); Auerbach et al., Nature 7375, 63-8 (2011); Barnes et al., J. Neurosci. 45, 15073-81 (2015); Bozdagi et al., Mol. Autism 1, 15 (2010); Tian et al., Nat. Neurosci. 2, 182-84 (2015); Wenger et al., Sci. Rep. 6, 19372 (2016)). Indeed, mGlu5-based therapies have been immensely successful at correcting FX in animal models (Bhakar et al., Ann. Rev. Neurosci. 45, 417-43 (2012)). To date, however, the results of human clinical trials in FX using mGlu5 negative allosteric modulators (NAMs) have been disappointing (Berry-Kravis et al., Sci. Transl. Med. 321, 321ra5 (2016); Scharf et al., Curr. Opin. Pharmacol. 20, 124-34 (2015)).